Cabergoline is the generic name of the compound 1-((6-allylergolin-8β-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea (Formula 1),
which belongs to the field of pharmaceutical agents for treatment of Parkinson's disease, restless legs syndrome, treatment of diseases like progressive supranuclear palsy and multisystematic atrophy. The compound was firstly described in the U.S. Pat. No. 4,526,892, Eur. J. Med. Chem., 24, 421 and GB-2,103,603-B reported the synthesis of cabergoline as well. II Farmaco, 50 (3), 175-178 (1995) firstly described crystalline cabergoline, later named cabergoline form I, which is unsolvated crystal form and was prepared as monocrystal from diethylether, Cabergoline was later described in several crystalline forms. The patent application WO 01/70740 describes form V as a toluene solvate and the process of its desolvatation into form I, WO 03/078392 describes form X as another toluene solvate and the process of conversion into form I. WO 01/72747 describes form II and its preparation. WO 01/72746 describes form VII and the process of preparing it. WO 04/101510 discloses amorphous cabergoline and several new crystalline forms of cabergoline such as form VIII (methyl tert-butyl ether solvate), form XI (xylene solvate), form XII (o-xylene solvate), form XIV (tetrahydropyrane solvate), form XV (cyclohexane solvate), form XVI (p-xylene solvate), form XVII (1,2,4-trimethylbenzene solvate), form XVIII (ethylbenzene solvate) and their preparation. WO 04/094368 discloses a new form of cabergoline (solvate form A (methyl tert-butyl ether solvate) and an amorphous form, free of crystalline cabergoline. WO 05/105796 describes an ethylbenzene solvate and WO 06/100492 several solvates with para disubstituted aromatic solvents as intermediates for preparation of form I. A process for preparing crystalline form I of cabergoline is described in WO 01/078433.
According to above mentioned literature cabergoline form I is in the form of plates, while repeating literature procedures for preparing form II and form VII gives agglomerates and thicker crystals. Crushing of hard thick crystals can lead to elevated temperatures which can decompose unstable material. Milling of softer material like the amorphous cabergoline often cause sticking of particles what lead to agglomerates and non-homogeneous material. On the other hand milling of the crystalline substance in the form of the needles using mechanical mills easily gives very fine material. Therefore, when low power is used for milling, the temperature of the substance during milling stays low and that prevents degradation of the product. There is no need for micronisation. Furthermore, when crystalline substance in the form of needles is used, this even means no milling in general, because the surface is not much enhanced by breaking needles as the longer side of the crystal possesses crucial part of the whole surface of needles. The surface of particles is responsible for physical contact in reaction environment what influences on the rate of dissolving and consequently on the dissolution profile and the kinetic parameters of a final dosage form.
It is generally known that the phenomena of agglomerates rarely appear in the case of crystal form where crystals are in the form of needles. Agglomerates include cavities which keep residual solvents and impurities from mother liquors. Removal of solvents and impurities from needles by washing and drying is easier and faster than from irregular particles and agglomerates what ensures better chemical quality.
Powdered and not agglomerated cabergoline is very suitable for preparation of the final dosage forms because it can be homogeneously incorporated into excipients what guarantees repeatable dissolution profile.
For pharmaceutical use there is a permanent need for preparation of active ingredients as much as possible free of impurities and solvents which are stable during technological operations of final dosage preparation and during storage up to its use for treatment in patients. Therefore the solvates with body unfriendly solvents are not suitable for pharmaceutical use, but only form I, form II and form VII are not characterized as solvates in literature. Thermodynamically stable crystal form is the most desirable form of active pharmaceutical ingredient from stability point of view. There is a constant need for preparation of thermodynamically stable cabergoline with low content of solvents. Said problem is solved within present invention disclosure.